title: MMP-2 is a disease-modifying gene in primary sclerosing cholangitis.
abstract: BACKGROUND
  Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the bile ducts, frequently necessitating orthotopic liver transplantation (OLT), often accompanied by inflammatory bowel disease (IBD). Matrix metalloproteinases (MMPs) are associated with fibrotic diseases caused by the involvement in tissue remodelling.
  
  
  OBJECTIVE
  To evaluate the contribution of MMP-2 and -9 promoter polymorphisms to disease severity in PSC, as assessed by death or need for OLT.
  
  
  METHODS
  Matrix metalloproteinase-2 (-1306 C/T) and -9 (-1562 C/T) gene promoter polymorphisms were analyzed in 132 PSC patients. Follow-up was from onset PSC until death, OLT or end of follow-up.
  
  
  RESULTS
  Twenty-year cumulative incidence (CI) of death or OLT for PSC patients with MMP-2 CT genotype was 86.5% compared to 52.8% for CC genotype (P = 0.030) and reached 100% at 11.3 years for TT genotype. In patients with IBD, CIs were similar: 20-years CI of death or OLT for MMP-2 CT genotype was 86.0% compared to 49.0% for CC genotype and 100% at 11.3 years for TT genotype. Patients without IBD showed a similar trend in 20 years CI for MMP-2 CT (77.8%) compared to CC (57.8%) and CI for TT genotype reached 100% at 9.3 years. Multivariate analysis showed, along with age at diagnosis, a stepwise increase in hazard ratio for MMP-2 T-allele polymorphism for death or OLT. MMP-9 genotype was not associated with disease severity in PSC.
  
  
  CONCLUSIONS
  Matrix metalloproteinase-2 C to T-1306 gene promoter polymorphism in PSC is an independent risk factor for disease severity as reflected by the need for OLT or disease progression leading to mortality.
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Kerem Sebib
authors.initials: KS
authors.lastname: Korkmaz
authors.forename: Bert-Jan F
authors.initials: BJ
authors.lastname: de Rooij
authors.forename: Bart
authors.initials: B
authors.lastname: van Hoek
authors.forename: Marcel
authors.initials: M
authors.lastname: Janse
authors.forename: Minneke J
authors.initials: MJ
authors.lastname: Coenraad
authors.forename: Johan J
authors.initials: JJ
authors.lastname: van der Reijden
authors.forename: Rinse K
authors.initials: RK
authors.lastname: Weersma
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Porte
authors.forename: Philip W
authors.initials: PW
authors.lastname: Voorneveld
authors.forename: Andrzej G
authors.initials: AG
authors.lastname: Baranski
authors.forename: Hein W
authors.initials: HW
authors.lastname: Verspaget
mesh_terms: D000367:Age Factors; D015209:Cholangitis, Sclerosing / Q000150:complications / Q000453:epidemiology* / Q000235:genetics*; D005838:Genotype; D006801:Humans; D015994:Incidence; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000453:epidemiology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D016016:Proportional Hazards Models; D012307:Risk Factors
chemical_list: C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: genotype; matrix metalloproteinase; orthotopic liver transplantation; primary sclerosing cholangitis